Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pleural Effusion in Children Review Article Keywords: children; pleural; effusion ABSTRACT Respiratory diseases including pleural effusions are a very common source of morbidity and mortality among children. The management of pleural effusion in children has been a topic of dispute between physicians and surgeons. This manuscript details up-to-date review of pleural effusion in children including medical modalities as well as surgical. A search of the pub-med database was carried out, using a combination of the following terms: pleural, effusion, and children. Different book chapters related to the topic were also reviewed. Keywords: lung; infection; pleura; children METHODS A search of the PubMed database was carried out, using different combinations of the following terms: pleural, effusion, and children; alteplase, streptokinase, pleural and effusion; urokinase, streptokinase, pleural, and effusion; urokinase, alteplase, pleural , and effusion; Video ,Assisted, Thoracoscopic, Surgery, firbinolytics, pleural and effusion. The initial search was conducted for manuscripts published between 2009 and 2014; however, the results were not adequate and we extended our search back to the year 1976. The primary search was designed to capture studies pertaining to our topic. Supplemental searches were also conducted. In addition, the searches were limited to studies on humans and published in English, and focused on children. After retrieval, each paper was read to verify relevance and appropriateness for review, based primarily on study design and ascertainment of necessary variables. We included randomized controlled trials (RCTs) and retrospective studies with adequate sample size; review articles were included as well. We excluded 11 articles because they did not fit our inclusion criteria. The search and selection of articles was conducted by Dr Hendaus, while Dr Janahi, an expert in the topic, approved the references. Meta-analysis was not conducted due to the limited published articles. For instance, part of our manuscript compares the efficacy among fibrinolytics, and the efficacy of Video Assisted Thoracoscopic Surgery compared to the use of fibrinolytics in the outcome of children with pleural effusion. Not too many articles touched on the comparisons mentioned above; hence Meta analysis was not practical. Therefore we opted for literature review. INTRODUCTION 1 Respiratory diseases are a very common source of morbidity and mortality among children [1].The mean age of children with pleural effusion and empyema is 3-6 years with 50-80% affecting males [2]. The development of empyema consists of three stages: Stage 1, also described as the early exudative phase, constitutes the collection of thin reactive fluid and few cells in the pleural space; stage 2, is described as the fibro-purulent phase, involves the formation of loculations; and Stage 3 is the organizing phase and it involves the creation of a thick layer of fibrin that encloses the lung [3]. The management of pleural effusion in children has been a topic of dispute between physicians and surgeons. Many treatment modalities have been suggested and applied, including intravenous antibiotics with or without thoracocentesis, chest drain insertion, intra-pleural fibrinolytics, and video-assisted thoracoscopic surgery (VATS). The different modes of management could be attributed to the variability in presentation of the disease [4]. Some authors believe that in the early stages of the disease, antibiotics and chest tube drainage should suffice [5] , but could be associated with high failure rate and prolonged hospital stay [4].However, advanced stages require decortication to allow lung re-expansion [6]. MICROBIOLOGY The probability to identify an organism in the pleural fluid specimens is low [7]. The British Thoracic Society recommends that Gram stain, AFB stain, and microbiologic culture be obtained on all pleural fluid samples [8]. In addition, nucleic acid amplification through polymerase chain 2 reaction (PCR) and antigen testing are indispensable tools in the detection of microorganisms and hence in the management of pleural effusion. It is recommended to obtain a pleural fluid white blood cell (WBC) count, with cell differential analysis to differentiate between bacterial, mycobacterial and malignancy etiologies [9]. Although different organisms can cause empyema S. pneumoniae is considered to be the most common cause [10]. Other causes are methicillin-sensitive Staphylococcus aureus (MSSA) [1112], and methicillin-resistant S. aureus (MRSA) [13]. Moreover, S. pyogenes, Haemophilus influenzae, Mycoplasma pneumoniae, Pseudomonas aureginosa, other Streptococcus spp and Mycobacterium tuberculosis have been reported [8]. IMAGING Chest Radiograph Chest radiography is usually the first imaging modality in the work up of parapneumonic effusion, but it cannot confirm the diagnosis. Chest radiograph might show early signs of parapnemonic effusion like obliteration of the costophrenic angle and a meniscus shape area up the lateral chest wall [14]. Ultrasonography 3 Ultrasonography is a safe mode of imaging and can be used to confirm the presence of pleural effusion [15]. A lenticular shape might imply the presence of a loculation when using the mode of ultrasonography [14]. Computed Tomography (CT) If the diagnosis of pleural effusion is not clear after performing a chest radiograph or a chest ultrasound, then chest CT will be the next step. For complicated cases of pleural effusion, it is also warranted because it can detect lung pathology and pulmonary abscess [16]. When ordering a Chest CT, intravenous contrast should be added to enhance pleural vision [15]. However, the disadvantages of a chest CT are the exposure of a patient to relatively high radiation [15], and the inability to visualize thin pleural septation or fibrin [17]. DIAGNOSTIC TAP If the health care provider suspects that the effusion is not of infectious etiology, then it will be recommended to perform a diagnostic tap for cytological analysis before chest drain insertion. In this case, you might be avoiding chest drain insertion and the complications associated with anaesthesia or sedation [8]. BIOCHEMISTRY/MICROSCOPY Fluid from bacterial infections, and sometimes tuberculosis, are predominantly neutrophils. On the other hand, lymphocytosis is detected in autoimmune diseases, tuberculosis, chylothorax and malignancy. If the fluid appears turbid, it is usually due to high cell count or high lipid content [18]. 4 Serous fluids are categorized into transudates and exudates. Transudative effusion usually refers to a non-inflammatory process (alteration of hydrostatic or colloid osmotic pressure), where it infers from ultrafiltration process across a membrane. It is usually low in protein [19]. On the other hand, exudates refer to an inflammation or inflammatory process, where it infers capillary permeability [19].A pleural fluid:serum protein ratio greater than 0.5, a pleural fluid LDH activity above 200U/L or a pleural fuid:serum LDH ratio greater than 0.6 is usually diagnostic of exudative effusion [19]. However, other authors state that pleural fluid parameters, such as glucose, protein, lactate dehydrogenase levels and pH are not recommended since they don’t change the management of pleural effusion [9]. MANAGEMENT Prevention The preferred treatment of pleural effusion is prevention via proper immunization [18]. Antibiotics Use Many practitioners use the option of antibiotics alone when managing a small pleural effusion in patients with no respiratory distress. Although it is an acceptable option, further intervention must be followed if the effusion is enlarging or patient is deteriorating [8, 20]. The initial treatment of all pleural effusion should be the use of antibiotics. For children with small effusions (less than 10 mm on lateral decubitus chest radiograph or opacification of less than one-fourth of the hemithorax), the choice of broad spectrum antibiotics, chest radiographs and good clinical exam should suffice on an outpatient basis [9]. 5 Children with larger pleural effusion should be hospitalized and the use of intravenous antibiotics is warranted [8]. Intravenous cefotaxime or ceftriaxone could be used as empiric treatment until cultures results are known. Clindamycin or vancomycin could be added for community acquired methicillin resistant (CA-MRSA) is suspected [9]. The current practice of first line empiric treatment of antibiotics is cefotaxime plus vancomycin because of the increased prevalence of drug resistant organisms [21]. The practitioner should be, however, aware of the most common causes of community acquired pneumonia in the area as a guidance towards the initial empiric treatment. For instance, ampicillin or penicillin G might also be considered as first-line drugs in fully immunized children in areas where local penicillin resistance in invasive strains of pneumococcus is uncommon [9]. For penicillin allergic patients, clindamycin should be used. Meropenem is an alternative if no improvement [22]. Different patients’ populations should be kept in mind. In children whom you suspect aspiration, coverage of anaerobes should be initiated. Coverage of gram-negative organisms in children with parapneumonic effusion due to nosocomial infection is also indicated [21]. As far as Mycobacterium tuberculosis, treatment is warranted only if the index of suspicion is high [8]. After initiating antibiotics empiric management, follow the culture results. If the culture is positive, then narrow the coverage according to the organism identified [22]. 6 Unfortunately, there are high proportions of cultures that come back negative, so the recommendation is to continue the initial blind antibiotic treatment, especially if the patient is clinically improving. The duration of treatment differs among practitioners, but the majority of medical centers continue the intravenous antibiotics until the patient is afebrile or when the chest tube is removed. Usually amoxicillin-clavulanic acid is given at discharge for 1-4 weeks, but definitely longer if needed [8]. Thoracocentesis and Chest Tube There was a debate whether thoracocentesis will suffice in terms of managing pleural effusion or whether going straight to chest tube insertion is the preferred option. In small effusions, thoracocentesis would be helpful in fluid aspiration and hence guidance towards the appropriate antibiotic use. Simple needle thoracocentesis is an option for older children, but if repeated thoracocentesis is required, then chest tube will be the better choice [8]. Small tubes (8-12 French) are reported as good as larger tubes [18].The indications for chest tube drainage as recommended by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America [9] are as follow: There is no indication for chest tube insertion in pleural effusion less than 10 mm on a lateral decubitus radiograph or if the opacification constitutes less than one-fourth of the hemithorax. There is no indication for chest tube insertion in pleural effusion if there is more than 10 mm of fluids but the opacification constitutes less than half of the hemithorax, the effusion is not consistent with empyema and if the patient is not in respiratory distress. 7 Chest tube is definitely indicated in opacities larger than half of the hemithorax and with quantity of fluids of more than 10 mm in children with respiratory distress and fluid consistent with empyema. However, in a study conducted by Shoseyov et al, stated that there is no difference between repeated ultrasound-guided needle thoracocentesis (RUSGT) and Chest tube insertion in terms of mean duration of temperature, mean fluid drained, duration of antibiotic use and duration of hospitalization stay [23]. The insertion of a chest tube should also be considered if there is failure to respond to 48 to 72 hours of antibiotic therapy, hypoxia, hepercapnia, large amounts of free flowing pleural fluid and if there is evidence of fibropurulent effusions (pH <7.0, glucose <40 mg/dL [2.22 mmol/L], LDH >1000 IU [16.67 kat/L] [21]. Fribrinolytics The use of intrapleural fibrinolytics is being used with success worldwide for the management of complicated pleural effusions and empyema. Its use improves drainage without systemic fibrinolysis or hemorrhage. The worldwide success has been reported between 44% and 100% [24]. 8 The British Thoracic Society (BTS) and the American Pediatric Surgical Association suggest fibrinolytic therapy as a component of the medical option for patients in whom the pleural fluid is thick or loculated [8, 25]. The three fibrinolytics that have been in use are streptokinase, urokinase, and tissue plasminogen activator (tPA) [26]. Urokinase(UK) UK is a fibrinolytic agent that specifically catalyzes the cleavage of the arginine–valine bond in plasminogen [27]. BTS [8] and PIDS [9] (Pediatric Infectious disease society) recommend the usage of urokinase as follows: 40,000 units in 40 mL 0.9 percent saline for children one year and older, and 10,000 units in 10 mL 0.9 percent saline for children younger than 1 year. This dose should be administered twice daily (with a four-hour dwell time) for three days; if the response is not adequate, then additional doses can be administered after six doses. Intrapleural bupivacaine (0.5 to 1.0 mL/kg of a 0.25 percent solution) can be used for pain control. A multicentre randomized placebo controlled trial in children [28], showed that the length of hospital stay was shorter with the use of UK compared to patients where normal saline was administered. Stefanutti et al [29] also supported the use of UK and their study showed that 9 intrapleural urokinase has been shown to be effective in the treatment of pleural effusions in children. Streptokinase Streptokinase has same mechanism of action like UK; however, it is of bacterial origin rather than a recombinant human enzyme [29].The recommended dose is 12,300 to 136,000 U/kg per dose diluted to 50 ml volume with sterile saline solution into the intrapleural space via chest tube over 5 minutes [30]. In a study published by Yao et al showed that intrapleural fibrinolytic treatment with streptokinase is safe and effective and it can avert the need for surgery in most cases. Safety was reported as no major side effects after streptokinase instillation while efficacy was measured by Pleural fluid drainage which was almost four times higher in the streptokinase group compared to the control group [31]. Since streptokinase is of bacterial origin, possible side effects are fever, allergic reactions, and anti-streptokinase antibody production [30, 32-33]. Tissue plasminogen activator (tPA) TPA binds to fibrin in a thrombus then converts the entrapped plasminogen to plasmin, and finally initiates local fibrinolysis. Alteplase's serum half-life is 4-6 minutes, but can be prolonged when alteplase is bound to fibrin in a clot. The instillation of intrapleural tPA usually does not lead to plasma pharmacologic concentrations [34]. 10 The recommended dose of intrapleural tPA is 4 mg in 40 mL of normal saline. The first dose is given at the time of chest tube placement with 1 hour dwell time; the dose can be repeated once daily for 3 days (total of 3 doses) [21]. A study conducted at the Hospital for Sick Children in Toronto, Canada showed that intrapleural tPA led to a higher pleural fluid drainage compared to normal saline (691 mL vs 360 mL). The duration of chest tube placement was 84 hours for the early administration of intrapleural tPA group compared to 130 hours for the control group. The authors did not report local or systemic bleeding after intra-pleural tPA administration [35]. So which fibrinolytic to use? The efficacy of fibrinolytics use might reach 90% [36-37].Urokinase and streptokinase has the same effectiveness in treating complicated pleural effusions and empyemas [24]. Although it has a higher cost, urokinase is preferred over streptokinase due to its lower allergenic risk [29]. Urokinase and alpteplase were compared in a retrospective review study that included 71 children with pleural fluid effusion.The study concluded that Primary treatment success was 98% for alteplase and 100% for urokinase, with no major complications. However, pleural fluid drainage was higher with alteplase than urokinase during the 1st and 2nd days of fibrinolytic therapy, and for the duration of thoracostomy drainage [38]. In the literature review, there were no randomized studies comparing the effectiveness of streptokinase and alteplase in managing complicated pleural effusion. 11 VATS (Video-assisted thoracic surgery) Quite a few pediatric surgeons consider primary surgical intervention as the best mode of managing pleural effusion [39].However, there is so far not enough data to support their approach [3]. It is warranted to consult surgeons if there is failure of chest tube drainage, antibiotics and fibrinolytics. Surgical approach is also needed if the patient has persisting sepsis in combination with a persistent pleural effusion after the use of antibiotics and chest tube drainage. In addition, surgery is required in cases of empyema with significant lung pathology, bronchopleural fistula with pyopneumothorax, and secondary empyema [8]. VATS is usually indicated for drainage of purulent material, decortications of the fibropurulent septa, irrigation of the pleural cavity and visualization of the evacuation to allow re-expansion of the lung [40]. Fibrinolytics vs. VATS A study done by Kilic et al [36] suggests that intrapleural fibrinolytic treatment is an effective and safe in children with thoracic empyema and can obviate a thoracotomy in most cases. In a second study, in which 60 children were randomized to receive either percutaneous chest drain with intrapleural urokinase or video-assisted thoracoscopic surgery (VATS);the authors concluded that urokinase treatment is the better economic ,while no difference in clinical outcome between the 2 groups was noted [41].In addition St. Peter el al [42] showed that the 12 outcome data showed no difference in days of hospitalization after intervention, days of oxygen requirement, days until afebrile, or analgesic requirements. Faber et al [43] echoed the non-operative approach as effective. The study evaluated 75 pediatric empyema cases and it showed that non-operated children were admitted to the PICU less frequently than those who were operated and there was no significant statistical difference in overall hospitalization. On the other hand, Cohen et al [39] conducted a systematic review that showed the superiority of primary operative therapy compared with non-operative approaches. Operative management was associated with a lower mortality rate, lower re-intervention rate, shorter length of hospitalization, decreased time with a thoracostomy tube, and shorter course of antibiotic therapy, compared with non-operative therapy. A Cochrane Systematic Review on surgical versus non-surgical management of pleural empyema conducted by Coote et al[44] was also in favor of the operative approach showing that surgical group had higher primary treatment success. In addition, the study showed that all streptokinase medical failures required VATS and surgical patients had shorter hospital stay. In a large study, Shah et al included 3500 patients with pleural effusion that underwent different procedures: chest tube without fibrinolysis (n = 1762), chest tube with fibrinolysis (n = 623), VATS (n = 408), and thoracotomy (n = 797). The study concluded that length of stay was similar in patients that underwent VATS and chest tube insertion with or without fibrinolysis [45]. 13 Outcome and Prognosis Children with pleural effusion usually do well and their lung functions return to normal in the majority of children regardless of the management mode of pleural effusion [46], though some studies showed minor asymptomatic restrictive [47] or obstructive[46] abnormalities. Follow Up Children with pleural effusion should be seen for follow up within 4–6 weeks of discharge; the timing depends on the child’s clinical status at discharge [8].Chest radiography findings are abnormal at discharge, and a radiograph should be obtained at 4-6 weeks [8] .Complete radiological resolution is usually expected by 3-6 months [5,24]. Summary and Recommendations A conscientious path must be followed when managing a case of pleural effusion in children. The severity of the case and the progress of the disease usually dictate the approach. Antibiotics Use All infants and children with pleural effusion should be initiated on broad-spectrum antibiotics. If the organism is known, then narrowing the antibiotic spectrum is recommended. If the patient is hospitalized, then Intravenous antibiotics should be continued until the child is afebrile. Oral antibiotics such as amoxicillin-clavulanic acid are then given at discharge for 1–4 weeks, but longer if there is residual disease. For atypical cases such as non-bacterial pleural effusion or suspected tuberculosis, a consultation with the specialist will be warranted. Imaging A plain chest film should be the initial imaging test. A lateral/decubitus view might help in the diagnosis. Chest ultrasound will confirm the pleural fluid and might show loculations . Chest CT should be reserved for the complicated or doubtful cases to avoid unnecessary radiation exposure. 14 Chest Tube Chest tube is definitely indicated in opacities larger than half of the hemithorax and with quantity of fluids of more than 10 mm in children with respiratory distress and fluid consistent with empyema. Fibrinolytics Intrapleural administration of fibrinolytics is an effective treatment for complicated parapneumonic effusions and pleural empyemas (pleural effusion is thick or loculated). Any of the three of fibrinolytics can be used (urokinase, streptokinase and alteplase); however, urokinase is the most studied among the three options and is probably the preferred agent if available. VATS Patients should be considered for surgical treatment if they have persisting sepsis in association with a persistent pleural collection, despite chest tube drainage, fibrinolytics and antibiotics use. Follow up Children with pleural effusion or empyema should be seen for follow up within 4–6 weeks of discharge. Chest radiographs are usually abnormal at discharge, and a radiograph should be obtained after 4-6 weeks. LIMITATIONS Our manuscript portrays a comprehensive review of pleural effusion in children, especially the management options. However, our limitation was the inability to conduct a Meta-analysis; this is mostly attributed to the lack of published articles comparing different modes of management of pleural effusion in children. 15 References . 1. Williams BG, Gouws E, Boschi-Pinto C, Bryce J, Dye C: Estimates of world-wide distribution of child deaths from acute respiratory infections. Lancet Infect Dis 2002, 2(1):25-32. 2. Nyambat B, Kilgore PE, Yong DE, Anh DD, Chiu CH, Shen X, et al. Survey in childhood empyema in Asia:Implications for detecting the unmeasured burden of culture negative bacterial disease . BMC Infectious diseases. 2008; 8:90 3. Avansino JR, Goldman B, Sawin RS, Flum DR. Primary Operative Versus Nonoperative Therapy for Pediatric Empyema: A Meta-analysis. Pediatrics. 2005 Jun; 115(6):1652-9. 4. Chan W, Keyser-Gauvin E, Davis GM, Nguyen LT, Laberge JM. Empyema thoracis in children: a 26-year review of the Montreal Children’s Hospital experience. J Pediatr Surg 1997; 32:870-2. 5.Chan PW, Crawford O, Wallis C, Dinwiddie R. Treatment of pleural empyema. J Paediatr Child Health. Aug 2000;36(4):375-7. 6. Fraga JC, Kim P. Surgical treatment of parapneumonic pleural effusion and its complications. J Pediatr (Rio J) 2002;78: S161-70 7. Barnes TW, Olson EJ, Morgenthaler TI, Edson RS, Decker PA, Ryu RH. Low Yield of Microbiologic Studies on Pleural Fluid Specimens. CHEST. 2005 ;127 (3):916-921 8. Balfour-Lynn IM, Abrahamson E, Cohen G, Hartley J, King S, Parikh D, et al . BTS guidelines for the management of pleural infection in children .Thorax. 2005 Feb;60 Suppl 1:i1-21. 9. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C,et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011 16 Oct;53(7):617-30. 10. Spencer DA, Iqbal SM, Hasan A, Hamilton L: Empyema thoracis is still increasing in UK children. Bmj 2006, 332(7553):1333. 11. Baranwal AK, Singh M, Marwaha RK, Kumar L. Empyema thoracis: a 10-year comparative review of hospitalised children from south Asia. Arch Dis Child. 2003;88:1009–14. 12.Hernández-Bou S, Garcia-Garcia JJ, Esteva C, Gene A, Luaces C, Almagro CM. Pediatric parapneumonic pleural effusion: epidemiology, clinical characteristics, and microbiological diagnosis. Pediatr Pulmonol. 2009; 44:192–200. 13. Len KA, Bergert L, Patel S, Melish M, Kimata C, Erdem G. Community-acquired Staphylococcus aureus pneumonia among hospitalized children in Hawaii. Pediatr Pulmonol. 2010; 45:898–905. 14. King S , Thomson A .Radiological perspectives in empyema. Br Med Bull.2002; 61:203–214 15. Calder A, Owens CM. Imaging of parapneumonic pleural Effusions And empyema in Children. Pediatr Radiol .2009 ;39:527–537 16.Parmar A, Peek G, Firmin R, Pandya H and Gaillard E. What is the role of chest computed tomography in children with parapneumonic effusion? Thorax 2010; 65:A111-A112 17. Evans AL , Gleeson FV. Radiology in pleural disease: state of the art. Respirology.2004; 9:300–312 18. Muzumdar H. Pleural effusion. Pediatrics in Review. 2012; 33 (1): 45-47 19. Tarn A, Lapworth R. Biochemical analysis of pleural fluid: what should we measure? Ann Clin Biochem 2001; 38: 311-322 20. Jaffé A, Balfour-Lynn IM. Management of empyema in children. Pediatr Pulmonol. 2005 Aug;40(2):148-56. 21. Janahi IA, Fakhoury K. In: Management and prognosis of parapneumonic effusion and empyema in children [webpage on the Internet] Basow DS, editor. Waltham, MA: UpToDate; 2012. [Accessed March 14, 2014.]. Available from: 17 http://www.uptodate.com/contents/management-and-prognosis-of-parapneumonic-effusion-andempyema-in-children 22. Davies CH, Gleeson FV, Davies RJO. BTS guidelines on the management of pleural infection. Thorax 2003; 58 (suppl II):ii39–ii52. 23. Shoseyov D, Bibi H, Shatzberg G, Klar A, Akerman J, Hurvitz H, et al. Short-term course and outcome of treatments of pleural empyema in pediatric patients: repeated ultrasound-guided needle thoracocentesis vs chest tube drainage. Chest. 2002. Mar;121(3):836-40 24.Uyan AP, Ozyürek H, Yilmaz E. Using of fibrinolytics in the treatment of complicated parapneumonic effusion and empyema in children. Tuberk Toraks. 2003;51(3):320-4. 25. Kokoska ER ,Chen MK. New Technology Committee. Position paper on video-assisted thoracoscopic surgery as treatment of pediatric empyema. J Pediatr Surg 2009; 44:289-93 26. Sahn SA. Management of complicated parapneumonic effusions. Am Rev Respir Dis 1993;148 :813–817. 27. Bennart NV and Francis JC. Mechanism of the urokinase catalyzed activation of human plasminogen. J. Biol. Chem. 1976; 251: 3906-3912. 28. Thomson AH, Hull J, Kumar MR , Wallis C, Balfour Lynn IM..Randomised trial of Intrapleral urokinase in the treatment of childhood empyema. Thorax 2002. Apr;57(4):343-7. 29. Stefanutti G, Ghirardo V, Barbato A, Gamba P. Evaluation of a pediatric protocol of intrapleural urokinase for pleural empyema: a prospective study. Surgery 2010 Sep;148(3):58994. Epub 2010 Mar 20. 30. Rosen H, Nadkarni V, Theroux M, Padman R, Klein J.. Intrapleural streptokinase as adjunctive treatment for persistent empyema in pediatric patients. Chest 1993;103:1190-3. 31. Yao CT, JWu JM, Liu CC, Wu MH, Chuang HY, Wang JN.Treatment of Complicated Parapneumonic Pleural Effusion With Intrapleural Streptokinase in Children. Chest 2004;125;566-571 32. Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson FV, Miller R, et al. U.K. Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med 2005;352:865-74. 18 33. Bouros D, Schiza S, Patsourakis G, Chalkiadakis G, Panagou P, Siafakas NM. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med 1997;155:291-5. 34. Assefa ,D (2011,October 5). Pediatrics Pleural effusion. Retrieved May 3, 2014 from http://emedicine.medscape.com/article/1003121-overview#showall 35. Weinstein M, Restrepo, R, Chait P, Connolly B, Temple M, Macarthur C. Effectiveness and Safety of Tissue Plasminogen Activator in the Management of Complicated Parapneumonic Effusions. Pediatrics 2004 ;113(3):e182 -e185 36. Kilic N, Celebi S, Gurpinar A, Hacimustafaoglu M, Konca Y, Ildirim I, et al. Management of thoracic empyema in children. Pediatr Surg Int. Jan 2002; 18(1):21-3. 37. Barbato A, Panizzolo C, Monciotti C, Marcucci F, Stefanutti G, Gamba PG. Use of urokinase in childhood pleural empyema. Pediatr Pulmonol. Jan 2003; 35(1):50-5. 38. Wells R, Havens P. Intrapleural Fibrinolysis for Parapneumonic Effusion and Empyema in Children. Radiology 2003; 228:370–378 39. Cohen G, Hjortdal V, Ricci M, Jaffe A, Wallis C, Dinwiddie R,et al. Primary thoracoscopic treatment of empyema in children. J Thorac Cardiovasc Surg 2003;125 :79– 83 40. Kalfa N, Allal H, Montes-Tapia F, Lopez M, Forgues D, Guibal MP, et al. Ideal timing of thoracoscopic decortication and drainage for empyema in children. Surg Endosc 2004;18:472-7. 41.Sonappa S, Cohen G, Owens CM, Van Doorn C, Cairns J, Stanojevic S, et al. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Am J Respir Crit Care Med. Jul 15 2006;174(2):221-7. 42.St Peter SD, Tsao K, Spilde TL, Keckler SJ, Harrison C, Jackson MA, et al. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial. J Pediatr Surg. Jan 2009;44(1):106-11; discussion 111 43. Faber DL, Best LA, Orlovsky M, Lapidot M, Nir RR, Kremer R. Streptokinase Fibrinolysis Protocol: The Advantage of a Non-Operative Treatment for Stage II Pediatric Empyema Patients. IMAJ 2012 ;14 (3): 157-161 19 44. Coote N, Kay E. Surgical versus non-surgical management of pleural empyema (Cochrane Review). In: The Cochrane Library, Issue 1. Chichester, UK: John Wiley & Sons, 2007. 45. Shah SS, Hall M, Newland JG, Brogan TV, Farris RW, Williams DJ, et al. Comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood. J Hosp Med 2011; 6(5):256-63 46. Redding GJ, Walund L, Walund D, Jones JW, Stamey DC, Gibson RL. Lung function in children following empyema. Am J Dis Child 1990;144:1337–42. 47. Sarihan H, Cay A, Aynaci M, Akyazici R, Baki A.. Empyema in children. Eur J Cardiovasc Surg 1998; 39:113–6. Table 1. Fibrinolytics used and their recommended doses Urokinase(UK) Streptokinase Tissue plasminogen activator (tPA) *40,000 units in 40 mL 0.9 percent saline for children one year and older. 12,300 to 136,000 U/kg per dose diluted to 50 ml volume with sterile saline solution The recommended dose of intrapleural tPA is 4 mg in 40 mL of normal saline. The first dose is given at the time of chest tube placement with 1 hour dwell time; the dose can be repeated once daily for 3 days (total of 3 doses) *10,000 units in 10 mL 0.9 percent saline for children younger than 1 year. *It should be administered twice daily (with a fourhour dwell time) for three days; if the response is not adequate, then additional doses can be administered after six doses. 20